Glycopyrrolate is an antimuscarinic agent which is useful in the treatment of conditions such as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF) and related airway diseases. Glycopyrrolate is also useful as a heart rate lowering agent when administered by inhalation to patients, in particular patients with conditions such as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF) and related airway diseases. It is known to provide glycopyrrolate formulations in the form of dry powder formulations, for administration using dry powder inhalers. Frequently salts of glycopyrrolate are used, such as glycopyrronium bromide.
Glycopyrrolate is commercially available or may be prepared using the method described in U.S. Pat. No. 2,956,062. The most physically stable configuration is when the particles are crystalline and they contain few amorphous regions on their surfaces.
Glycopyrrolate has been found to have an acute problem with respect to its stability, especially immediately following a conventional micronisation process.
Micronisation of glycopyrrolate involves the milling of a relatively coarse source powder into a system which involves multiple high-speed or high energy collisions. Typically, source powders of unmicronised glycopyrrolate will exist in particle sizes substantially greater than 10 μm, with typical distributions resembling D10>10 μm, D50>90, D90>250 μm. The primary objective of the micronisation process is to reduce the primary particle size to a size which is small enough to be delivered to the respiratory airways. For example, it is known that a suitable size may be where the majority of the particles as measured by mass or volume fall within the inhalable range of 0.1 μm to 10 μm, preferably 0.1 μm to 6 μm or more preferably 0.5 μm to 5 μm.
The multiple collisions that occur with high-speed or high energy micronisation provide the milling action which is required to break the particles down to the appropriate size. It is also well known that such milling action may also induce the generation of non-crystalline material, especially on the surface of the particles where particles have collided either with each other as in the case of jet milling, or with the milling medium as in the case of ball milling, or with the milling machine as in the case of knife milling. Such non-crystalline material may be amorphous material.
The presence of non-crystalline or amorphous regions in glycopyrrolate material can lead to significant physical instability.
International patent application WO2001076575 discloses a pharmaceutical composition for pulmonary delivery comprising glycopyrrolate in a controlled release formulation, wherein, on administration, the glycopyrrolate exerts its pharmacological effect over a period greater than 12 hours.
US publication number US 2014/0080890 discloses glycopyrrolate for use as a heart rate lowering agent and more particularly, but not exclusively, for use in patients suffering from respiratory conditions such as chronic obstructive pulmonary disease. It discloses conducting micronisation under increased Relative Humidity (RH) to reduce the formation of amorphous material.
International patent application WO2005105043 discloses dry powder compositions which exhibit improved stability over time, and methods for producing the same.
International patent application WO2008000482 discloses a process for preparing dry powder formulations of a glycopyrronium salt for inhalation that have good stability. The process involves (a) micronising a glycopyrronium salt together with an anti-adherent agent, and (b) admixing carrier particles to form the dry powder formulation.
International patent application WO2008000482 discloses a process for reducing the tendency of a drug substance to aggregate and/or agglomerate during storage. The process involves micronising the drug substance to give a mean particle size of less than about 10 μm, and exposing the micronised drug substance to a dry environment at an elevated temperature between 40° C. and 120° C. for at least six hours.
It has been also suggested that conducting micronisation with humidified air or other gas may help to reduce the generation of amorphous materials. Both WO1999054048 and WO2000032165 disclose that milling crystalline particles, especially medicament powders intended for administration by inhalation under increased humidity can reduce the generation of amorphous material.
WO2000032313 discloses the milling of highly crystalline material, exemplified with triamcinolone acetonide at reduced temperature using helium or a mixture of helium and another gas in order to reduce the formation of amorphous material.